The present invention relates to spirocyclic cyclohexane compounds, to processes for the preparation thereof, to pharmaceutical compositions comprising these compounds and to the use of spirocyclic cyclohexane compounds in the preparation of pharmaceutical compositions.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid-receptor-like) receptor (Meunier et al., Nature 377, 1995, p. 532-535) which belongs to the family of the opioid receptors and is to be found in many regions of the brain and of the spinal cord and exhibits a high affinity for the ORL1 receptor. The ORL1 receptor is homologous with the μ, κ and δ opioid receptors, and the amino acid sequence of the nociceptin peptide exhibits a strong similarity with those of the known opioid peptides. The activation of the receptor induced by nociceptin leads, via coupling with Gi/o proteins, to inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532-535).
After intercerebroventicular administration, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792-794). These findings can be explained as inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, p. 333-337). In this connection, nociceptin has also been shown to have anxiolytic activity (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand, nociceptin has also been shown to have an antinociceptive effect in various animal models, especially after intrathecal administration. Nociceptin has an antinociceptive action in various models of pain, for example in the tail-flick test in the mouse (King et al., Neurosci. Lett., 223, 1997, 113-116). In models for neuropathic pain, it has likewise been possible to demonstrate an antinociceptive action for nociceptin, which is of particular interest in that the effectiveness of nociceptin increases after axotomy of spinal nerves. This is in contrast to conventional opioids, whose effectiveness diminishes under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
The ORL1 receptor is additionally also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al., Nature, 394, 1997, p. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and numerous further processes. In an overview article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261-1283), an overview is given of the indications or biological processes in which the ORL1 receptor plays or with high probability might play a role. Those mentioned are, inter alia: analgesia, stimulation and regulation of food intake, influence on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter secretion, especially of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhoea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is furthermore discussed.
The possible applications of compounds that bind to the ORL1 receptor and activate or inhibit it are correspondingly many and varied. In addition, opioid receptors such as the μ-receptor and the other subtypes of these opioid receptors, namely δ and κ, play a large part in the therapy of pain as well as in other of the mentioned indications. It is accordingly advantageous if the compounds also exhibit activity in respect of these opioid receptors.
WO 2004043967 discloses spirocyclic cyclohexane compounds which have a high affinity for the ORL1 receptor but also for the μ-opioid receptor. WO 2004043967 also describes, generically, a group in which R3 denotes alkyl or cycloalkyl. However, no exemplary compounds that are part of this sub-group are disclosed.
Solubility is an important property for bioavailability and a significant factor in respect of the effectiveness and therefore also the success of a pharmaceutical composition. Complex processes are used to increase the solubility, for example the preparation of micro- or nano-particles (e.g. Exp. Op. Dug Disc. 2007, 2, 145); however, it is simpler and more predictable to develop compounds which have a higher solubility while being equally as effective.
A disadvantage of the example compounds disclosed in WO 2004043967 is the poor solubility of the compounds.